Obesity wars: hypothalamic sEVs a new hope
Authors: Sayani Mukherjee, Carlos Diéguez, Johan Fernø, Miguel López
Journal: Trends in Molecular Medicine (2023)

There are three main weaknesses in the available antiobesity treatments: (i) lack of specificity and therefore harmful side effects, (ii) unknown mechanism of action in many cases, and (iii) they mainly target either intestinal absorption or feeding/appetite and not energy expenditure.Small extracellular vesicle (sEV)-based therapeutics are already undergoing clinical trials, although as yet no sEV-based therapy has been approved by the FDA.Targeting of specific sets of hypothalamic neurons with engineered sEVs would provide: (i) increased specificity and therefore reduced side effects, (ii) knowledge of the mechanism of action, and (iii) an integral targeting of energy balance, modulating both feeding and energy expenditure.Current preclinical evidence has demonstrated that specific targeting of hypothalamic cell populations using sEVs ameliorates diet-induced and genetic obesity. There are currently several pharmacological therapies available for the treatment of obesity, targeting both the central nervous system (CNS) and peripheral tissues. In recent years, small extracellular vesicles (sEVs) have been shown to be involved in many pathophysiological conditions. Because of their special nanosized structure and contents, sEVs can activate receptors and trigger intracellular pathways in recipient cells. Notably, in addition to transferring molecules between cells, sEVs can also alter their phenotypic characteristics. The purpose of this review is to discuss how sEVs can be used as a CNS-targeted strategy for treating obesity. Furthermore, we will evaluate current findings, such as the sEV-mediated targeting of hypothalamic AMP-activated protein kinase (AMPK), and discuss how they can be translated into clinical application. There are currently several pharmacological therapies available for the treatment of obesity, targeting both the central nervous system (CNS) and peripheral tissues. In recent years, small extracellular vesicles (sEVs) have been shown to be involved in many pathophysiological conditions. Because of their special nanosized structure and contents, sEVs can activate receptors and trigger intracellular pathways in recipient cells. Notably, in addition to transferring molecules between cells, sEVs can also alter their phenotypic characteristics. The purpose of this review is to discuss how sEVs can be used as a CNS-targeted strategy for treating obesity. Furthermore, we will evaluate current findings, such as the sEV-mediated targeting of hypothalamic AMP-activated protein kinase (AMPK), and discuss how they can be translated into clinical application. Environmental and genetic factors interact with global food system drivers to create wide variations in the prevalence of obesity (see Glossary) among populations [1.Loos R.J.F. Yeo G.S.H. The genetics of obesity: from discovery to biology.Nat. Rev. Genet. 2022; 23: 120-133Crossref PubMed Scopus (179) Google Scholar, 2.Dragano N.R.V. et al.Recent updates on obesity treatments: available drugs and future directions.Neuroscience. 2020; 437: 215-239Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar, 3.Muller T.D. et al.Anti-obesity drug discovery: advances and challenges.Nat. Rev. Drug Discov. 2022; 21: 201-223Crossref PubMed Scopus (150) Google Scholar, 4.Angelidi A.M. et al.Novel noninvasive approaches to the treatment of obesity: from pharmacotherapy to gene therapy.Endocr. Rev. 2022; 43: 507-557Crossref PubMed Scopus (15) Google Scholar, 5.Müller T.D. et al.Anti-obesity therapy: from rainbow pills to polyagonists.Pharmacol. Rev. 2018; 70: 712-746Crossref PubMed Scopus (97) Google Scholar]. Future predictions are alarming, with overweight – body mass index (BMI) ≥25 – and obesity (BMI ≥30) estimated to reach pandemic proportions [1.Loos R.J.F. Yeo G.S.H. The genetics of obesity: from discovery to biology.Nat. Rev. Genet. 2022; 23: 120-133Crossref PubMed Scopus (179) Google Scholar, 2.Dragano N.R.V. et al.Recent updates on obesity treatments: available drugs and future directions.Neuroscience. 2020; 437: 215-239Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar, 3.Muller T.D. et al.Anti-obesity drug discovery: advances and challenges.Nat. Rev. Drug Discov. 2022; 21: 201-223Crossref PubMed Scopus (150) Google Scholar, 4.Angelidi A.M. et al.Novel noninvasive approaches to the treatment of obesity: from pharmacotherapy to gene therapy.Endocr. Rev. 2022; 43: 507-557Crossref PubMed Scopus (15) Google Scholar, 5.Müller T.D. et al.Anti-obesity therapy: from rainbow pills to polyagonists.Pharmacol. Rev. 2018; 70: 712-746Crossref PubMed Scopus (97) Google Scholar]. Cancer, cardiovascular diseases, and type 2 diabetes (T2D) are among the direct and indirect comorbidities linked with obesity [1.Loos R.J.F. Yeo G.S.H. The genetics of obesity: from discovery to biology.Nat. Rev. Genet. 2022; 23: 120-133Crossref PubMed Scopus (179) Google Scholar, 2.Dragano N.R.V. et al.Recent updates on obesity treatments: available drugs and future directions.Neuroscience. 2020; 437: 215-239Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar, 3.Muller T.D. et al.Anti-obesity drug discovery: advances and challenges.Nat. Rev. Drug Discov. 2022; 21: 201-223Crossref PubMed Scopus (150) Google Scholar, 4.Angelidi A.M. et al.Novel noninvasive approaches to the treatment of obesity: from pharmacotherapy to gene therapy.Endocr. Rev. 2022; 43: 507-557Crossref PubMed Scopus (15) Google Scholar, 5.Müller T.D. et al.Anti-obesity therapy: from rainbow pills to polyagonists.Pharmacol. Rev. 2018; 70: 712-746Crossref PubMed Scopus (97) Google Scholar]. In terms of treating morbid obesity, bariatric surgery is undoubtedly the most effective intervention [6.Evers S.S. et al.The physiology and molecular underpinnings of the effects of bariatric surgery on obesity and diabetes.Annu. Rev. Physiol. 2017; 79: 313-334Crossref PubMed Scopus (73) Google Scholar,7.Akalestou E. et al.Mechanisms of weight loss after obesity surgery.Endocr. Rev. 2022; 43: 19-34Crossref PubMed Scopus (22) Google Scholar]. However, this surgery is highly invasive and not without risk for adverse effects, so it cannot be recommended for obesity-induced metabolic complications in the broader obese population, and it is currently applicable only for those who have BMI >40 or BMI >35 if comorbidities are present. Furthermore, surgery effectiveness varies from patient to patient, with many experiencing poor long-term results, such as reoccurrence of weight gain [6.Evers S.S. et al.The physiology and molecular underpinnings of the effects of bariatric surgery on obesity and diabetes.Annu. Rev. Physiol. 2017; 79: 313-334Crossref PubMed Scopus (73) Google Scholar,7.Akalestou E. et al.Mechanisms of weight loss after obesity surgery.Endocr. Rev. 2022; 43: 19-34Crossref PubMed Scopus (22) Google Scholar]. Pharmacological treatment represents an alternative strategy to surgery, and a growing number of innovative antiobesity drugs are being developed [2.Dragano N.R.V. et al.Recent updates on obesity treatments: available drugs and future directions.Neuroscience. 2020; 437: 215-239Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar, 3.Muller T.D. et al.Anti-obesity drug discovery: advances and challenges.Nat. Rev. Drug Discov. 2022; 21: 201-223Crossref PubMed Scopus (150) Google Scholar, 4.Angelidi A.M. et al.Novel noninvasive approaches to the treatment of obesity: from pharmacotherapy to gene therapy.Endocr. Rev. 2022; 43: 507-557Crossref PubMed Scopus (15) Google Scholar, 5.Müller T.D. et al.Anti-obesity therapy: from rainbow pills to polyagonists.Pharmacol. Rev. 2018; 70: 712-746Crossref PubMed Scopus (97) Google Scholar]. However, the main weaknesses of the currently available antiobesity treatments in the clinic are three: (i) low specificity and therefore undesired harmful side effects, (ii) in many cases unknown mechanism of action, and (iii) in most instances they exclusively target either intestinal absorption (with unpleasant side effects) or feeding/appetite, and therefore elicit a nonintegral approach to energy homeostasis [2.Dragano N.R.V. et al.Recent updates on obesity treatments: available drugs and future directions.Neuroscience. 2020; 437: 215-239Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar, 3.Muller T.D. et al.Anti-obesity drug discovery: advances and challenges.Nat. Rev. Drug Discov. 2022; 21: 201-223Crossref PubMed Scopus (150) Google Scholar, 4.Angelidi A.M. et al.Novel noninvasive approaches to the treatment of obesity: from pharmacotherapy to gene therapy.Endocr. Rev. 2022; 43: 507-557Crossref PubMed Scopus (15) Google Scholar, 5.Müller T.D. et al.Anti-obesity therapy: from rainbow pills to polyagonists.Pharmacol. Rev. 2018; 70: 712-746Crossref PubMed Scopus (97) Google Scholar] (Figure 1). Furthermore, it is well established that obesity is a heterogeneous condition regarding etiology, phenotype, and response to treatment [1.Loos R.J.F. Yeo G.S.H. The genetics of obesity: from discovery to biology.Nat. Rev. Genet. 2022; 23: 120-133Crossref PubMed Scopus (179) Google Scholar, 2.Dragano N.R.V. et al.Recent updates on obesity treatments: available drugs and future directions.Neuroscience. 2020; 437: 215-239Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar, 3.Muller T.D. et al.Anti-obesity drug discovery: advances and challenges.Nat. Rev. Drug Discov. 2022; 21: 201-223Crossref PubMed Scopus (150) Google Scholar, 4.Angelidi A.M. et al.Novel noninvasive approaches to the treatment of obesity: from pharmacotherapy to gene therapy.Endocr. Rev. 2022; 43: 507-557Crossref PubMed Scopus (15) Google Scholar, 5.Müller T.D. et al.Anti-obesity therapy: from rainbow pills to polyagonists.Pharmacol. Rev. 2018; 70: 712-746Crossref PubMed Scopus (97) Google Scholar]. Consequently, there is a need for personalized adaptions in obesity treatment. In this review we will discuss the advantage of nanotechnology-mediated drug delivery and assess the effectiveness of sEVs as nanocarriers to modulate specific hypothalamic neurons to combat obesity (Figure 1). For many people who live with obesity, lifestyle changes such as diets and physical exercise are not very effective in losing weight, and in recent years there has been an increased focus on pharmacotherapy options [2.Dragano N.R.V. et al.Recent updates on obesity treatments: available drugs and future directions.Neuroscience. 2020; 437: 215-239Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar, 3.Muller T.D. et al.Anti-obesity drug discovery: advances and challenges.Nat. Rev. Drug Discov. 2022; 21: 201-223Crossref PubMed Scopus (150) Google Scholar, 4.Angelidi A.M. et al.Novel noninvasive approaches to the treatment of obesity: from pharmacotherapy to gene therapy.Endocr. Rev. 2022; 43: 507-557Crossref PubMed Scopus (15) Google Scholar, 5.Müller T.D. et al.Anti-obesity therapy: from rainbow pills to polyagonists.Pharmacol. Rev. 2018; 70: 712-746Crossref PubMed Scopus (97) Google Scholar]. Several drugs have been developed to treat this disease, including phentermine-topiramate (a noradrenergic sympathomimetic amine), orlistat (a triacylglycerol lipase inhibitor), liraglutide [a glucagon-like peptide 1 (GLP-1) receptor (GLP-1R) agonist], lorcaserin (a selective serotonergic 2C receptor agonist), and naltrexone-bupropion (a noradrenaline and dopamine reuptake inhibitor/opioid receptor antagonist) [2.Dragano N.R.V. et al.Recent updates on obesity treatments: available drugs and future directions.Neuroscience. 2020; 437: 215-239Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar, 3.Muller T.D. et al.Anti-obesity drug discovery: advances and challenges.Nat. Rev. Drug Discov. 2022; 21: 201-223Crossref PubMed Scopus (150) Google Scholar, 4.Angelidi A.M. et al.Novel noninvasive approaches to the treatment of obesity: from pharmacotherapy to gene therapy.Endocr. Rev. 2022; 43: 507-557Crossref PubMed Scopus (15) Google Scholar, 5.Müller T.D. et al.Anti-obesity therapy: from rainbow pills to polyagonists.Pharmacol. Rev. 2018; 70: 712-746Crossref PubMed Scopus (97) Google Scholar]. The scope of this review is not to summarize the actions of these drugs, which has been reviewed elsewhere recently [2.Dragano N.R.V. et al.Recent updates on obesity treatments: available drugs and future directions.Neuroscience. 2020; 437: 215-239Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar, 3.Muller T.D. et al.Anti-obesity drug discovery: advances and challenges.Nat. Rev. Drug Discov. 2022; 21: 201-223Crossref PubMed Scopus (150) Google Scholar, 4.Angelidi A.M. et al.Novel noninvasive approaches to the treatment of obesity: from pharmacotherapy to gene therapy.Endocr. Rev. 2022; 43: 507-557Crossref PubMed Scopus (15) Google Scholar, 5.Müller T.D. et al.Anti-obesity therapy: from rainbow pills to polyagonists.Pharmacol. Rev. 2018; 70: 712-746Crossref PubMed Scopus (97) Google Scholar], but to emphasize that new treatment options are still warranted. The incretin GLP-1 has received enormous attention during the past decades as a therapeutic target for the treatment of obesity and T2D. Continuous improvement of the pharmacokinetic profile of GLP-1R agonists – starting from the natural hormone with a half-life of approximately 2–3 min, to the development of twice daily, and even once-weekly drugs – highlights the pharmaceutical evolution of GLP-1-based drugs [3.Muller T.D. et al.Anti-obesity drug discovery: advances and challenges.Nat. Rev. Drug Discov. 2022; 21: 201-223Crossref PubMed Scopus (150) Google Scholar,5.Müller T.D. et al.Anti-obesity therapy: from rainbow pills to polyagonists.Pharmacol. Rev. 2018; 70: 712-746Crossref PubMed Scopus (97) Google Scholar]. In peripheral organs, and in the brain as well, the agonism of the GLP-1R affects both energy and glucose homeostasis [3.Muller T.D. et al.Anti-obesity drug discovery: advances and challenges.Nat. Rev. Drug Discov. 2022; 21: 201-223Crossref PubMed Scopus (150) Google Scholar,5.Müller T.D. et al.Anti-obesity therapy: from rainbow pills to polyagonists.Pharmacol. Rev. 2018; 70: 712-746Crossref PubMed Scopus (97) Google Scholar,8.Beiroa D. et al.GLP-1 agonism stimulates brown adipose tissue thermogenesis and browning through hypothalamic AMPK.Diabetes. 2014; 63: 3346-3358Crossref PubMed Scopus (362) Google Scholar]. These drugs were originally developed for the treatment of T2D, and it is therefore noteworthy that the recently approved GLP-1R agonist semaglutide decreases body weight in obese or overweight subjects without diabetes by 14.9% in comparison to 2.4% for placebo-treated individuals [9.Wilding J.P.H. et al.Once-weekly semaglutide in adults with overweight or obesity.N. Engl. 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The significance of GIPR agonism in the treatment of obesity and diabetes recently re-emerged with the clinical success of unimolecular dual-agonists (targeting both GIPR and GLP-1R) with significantly improved body weight and glucose control in patients with obesity and T2D [9.Wilding J.P.H. et al.Once-weekly semaglutide in adults with overweight or obesity.N. Engl. J. Med. 2021; 384: 989-1002Crossref PubMed Scopus (713) Google Scholar, 10.Jastreboff A.M. et al.Tirzepatide once weekly for the treatment of obesity.N. Engl. J. Med. 2022; 387: 205-216Crossref PubMed Scopus (241) Google Scholar, 11.Frias J.P. et al.Efficacy and safety of LY3298176, a novel dual GIP and GLP-1 receptor agonist, in patients with type 2 diabetes: a randomised, placebo-controlled and active comparator-controlled phase 2 trial.Lancet. 2018; 392: 2180-2193Abstract Full Text Full Text PDF PubMed Scopus (423) Google Scholar]. 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This unimolecular balanced (equipotent) triple incretin, which combines the activities of GLP-1, GIP, and glucagon, decreases body weight and improves glycemic control in rodents and monkeys [16.Bossart M. et al.Effects on weight loss and glycemic control with SAR441255, a potent unimolecular peptide GLP-1/GIP/GCG receptor triagonist.Cell Metab. 2022; 34e10Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar]. Importantly, SAR441255 also improved glycemic control in healthy subjects [16.Bossart M. et al.Effects on weight loss and glycemic control with SAR441255, a potent unimolecular peptide GLP-1/GIP/GCG receptor triagonist.Cell Metab. 2022; 34e10Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar]. Results from other triagonists are needed to better understand the multiorgan and molecular mechanisms by which triple receptor agonism drives weight loss. The kind of therapeutic response obtained by these polyagonists is astonishing, being in a range only previously reached by bariatric surgery. As could be expected, the response to treatment varied considerably among the patients, with approximately 10% of patients not reaching the treatment goals in the latest clinical trial with tirzepatide [10.Jastreboff A.M. et al.Tirzepatide once weekly for the treatment of obesity.N. Engl. J. Med. 2022; 387: 205-216Crossref PubMed Scopus (241) Google Scholar]. Nevertheless, the results are still very promising, and the efficacy numbers of the drugs, when used in routine clinical practice, is eagerly awaited. A widespread belief is that hormone action in peripheral tissues is responsible for nutrient handling. However, a large body of evidence suggests that the CNS, and particularly the hypothalamus, contributes more to metabolic homeostasis throughout the body [17.Lopez M. et al.Hypothalamic AMPK: a canonical regulator of whole-body energy balance.Nat. Rev. Endocrinol. 2016; 12: 421-432Crossref PubMed Scopus (205) Google Scholar, 18.Jais A. Bruning J.C. Arcuate nucleus-dependent regulation of metabolism-pathways to obesity and diabetes mellitus.Endocr. Rev. 2022; 43: 314-328Crossref PubMed Scopus (34) Google Scholar, 19.Quarta C. et al.POMC neuronal heterogeneity in energy balance and beyond: an integrated view.Nat. Metab. 2021; 3: 299-308Crossref PubMed Scopus (48) Google Scholar] (Box 1). A key component of the hypothalamus is the arcuate nucleus (ARC), which regulates metabolism and feeding [17.Lopez M. et al.Hypothalamic AMPK: a canonical regulator of whole-body energy balance.Nat. Rev. Endocrinol. 2016; 12: 421-432Crossref PubMed Scopus (205) Google Scholar, 18.Jais A. Bruning J.C. Arcuate nucleus-dependent regulation of metabolism-pathways to obesity and diabetes mellitus.Endocr. Rev. 2022; 43: 314-328Crossref PubMed Scopus (34) Google Scholar, 19.Quarta C. et al.POMC neuronal heterogeneity in energy balance and beyond: an integrated view.Nat. Metab. 2021; 3: 299-308Crossref PubMed Scopus (48) Google Scholar]. ARC neurons are located near the median eminence, a circumventricular organ whose fenestrated capillaries leave a 'leaky' blood–brain barrier (BBB) [18.Jais A. Bruning J.C. Arcuate nucleus-dependent regulation of metabolism-pathways to obesity and diabetes mellitus.Endocr. Rev. 2022; 43: 314-328Crossref PubMed Scopus (34) Google Scholar,19.Quarta C. et al.POMC neuronal heterogeneity in energy balance and beyond: an integrated view.Nat. Metab. 2021; 3: 299-308Crossref PubMed Scopus (48) Google Scholar]. Consequently, the ARC receives hormonal, nutritional, and neuronal signals from the periphery and processes them in a coordinated manner to provide feedback. Two major neuronal clusters have been identified in the ARC: orexigenic neurons expressing neuropeptide Y (NPY) and agouti-related peptide (AgRP), and anorexigenic neurons expressing proopiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART) [17.Lopez M. et al.Hypothalamic AMPK: a canonical regulator of whole-body energy balance.Nat. Rev. Endocrinol. 2016; 12: 421-432Crossref PubMed Scopus (205) Google Scholar, 18.Jais A. Bruning J.C. Arcuate nucleus-dependent regulation of metabolism-pathways to obesity and diabetes mellitus.Endocr. Rev. 2022; 43: 314-328Crossref PubMed Scopus (34) Google Scholar, 19.Quarta C. et al.POMC neuronal heterogeneity in energy balance and beyond: an integrated view.Nat. Metab. 2021; 3: 299-308Crossref PubMed Scopus (48) Google Scholar] (Box 1). These first-order neurons sense peripheral metabolic hormones and nutrients, and contact second-order neurons in other hypothalamic sites, including the paraventricular (PVH) and ventromedial (VMH) nuclei, the lateral hypothalamic area (LHA), as well as autonomic preganglionic nerve cells in the brainstem and spinal cord [17.Lopez M. et al.Hypothalamic AMPK: a canonical regulator of whole-body energy balance.Nat. Rev. Endocrinol. 2016; 12: 421-432Crossref PubMed Scopus (205) Google Scholar, 18.Jais A. Bruning J.C. Arcuate nucleus-dependent regulation of metabolism-pathways to obesity and diabetes mellitus.Endocr. Rev. 2022; 43: 314-328Crossref PubMed Scopus (34) Google Scholar, 19.Quarta C. et al.POMC neuronal heterogeneity in energy balance and beyond: an integrated view.Nat. Metab. 2021; 3: 299-308Crossref PubMed Scopus (48) Google Scholar] (Box 1).Box 1Hypothalamic nucleus specificityThe hypothalamus is the brain region located below the thalamus, comprising the major portion of the ventral diencephalon [17.Lopez M. et al.Hypothalamic AMPK: a canonical regulator of whole-body energy balance.Nat. Rev. Endocrinol. 2016; 12: 421-432Crossref PubMed Scopus (205) Google Scholar, 18.Jais A. Bruning J.C. Arcuate nucleus-dependent regulation of metabolism-pathways to obesity and diabetes mellitus.Endocr. Rev. 2022; 43: 314-328Crossref PubMed Scopus (34) Google Scholar, 19.Quarta C. et al.POMC neuronal heterogeneity in energy balance and beyond: an integrated view.Nat. Metab. 2021; 3: 299-308Crossref PubMed Scopus (48) Google Scholar]. The role of the hypothalamus in the regulation of homeostasis is essential for survival and reproduction of the individual [17.Lopez M. et al.Hypothalamic AMPK: a canonical regulator of whole-body energy balance.Nat. Rev. Endocrinol. 2016; 12: 421-432Crossref PubMed Scopus (205) Google Scholar, 18.Jais A. Bruning J.C. Arcuate nucleus-dependent regulation of metabolism-pathways to obesity and diabetes mellitus.Endocr. Rev. 2022; 43: 314-328Crossref PubMed Scopus (34) Google Scholar, 19.Quarta C. et al.POMC neuronal heterogeneity in energy balance and beyond: an integrated view.Nat. Metab. 2021; 3: 299-308Crossref PubMed Scopus (48) Google Scholar]. One of the most remarkable features of the hypothalamus is its cytoarchitecture. Opposite to other brain areas, which are organized in layers (e.g., the cortex or the cerebellum, among others), the hypothalamus is organized in anatomically defined neuronal clusters called nuclei, forming interconnected neuronal circuits via axonal projections [17.Lopez M. et al.Hypothalamic AMPK: a canonical regulator of whole-body energy balance.Nat. Rev. Endocrinol. 2016; 12: 421-432Crossref PubMed Scopus (205) Google Scholar, 18.Jais A. Bruning J.C. Arcuate nucleus-dependent regulation of metabolism-pathways to obesity and diabetes mellitus.Endocr. Rev. 2022; 43: 314-328Crossref PubMed Scopus (34) Google Scholar, 19.Quarta C. et al.POMC neuronal heterogeneity in energy balance and beyond: an integrated view.Nat. Metab. 2021; 3: 299-308Crossref PubMed Scopus (48) Google Scholar]. Notably, the cellular specificity of the hypothalamus does not end with its organization in nuclei [17.Lopez M. et al.Hypothalamic AMPK: a canonical regulator of whole-body energy balance.Nat. Rev. Endocrinol. 2016; 12: 421-432Crossref PubMed Scopus (205) Google Scholar, 18.Jais A. Bruning J.C. Arcuate nucleus-dependent regulation of metabolism-pathways to obesity and diabetes mellitus.Endocr. Rev. 2022; 43: 314-328Crossref PubMed Scopus (34) Google Scholar, 19.Quarta C. et al.POMC neuronal heterogeneity in energy balance and beyond: an integrated view.Nat. Metab. 2021; 3: 299-308Crossref PubMed Scopus (48) Google Scholar]. Within each nucleus there are populations of neurons (and possibly glial cells) with genetic profiles and, what is more important, with different functions [17.Lopez M. et al.Hypothalamic AMPK: a canonical regulator of whole-body energy balance.Nat. Rev. Endocrinol. 2016; 12: 421-432Crossref PubMed Scopus (205) Google Scholar, 18.Jais A. Bruning J.C. Arcuate nucleus-dependent regulation of metabolism-pathways to obesity and diabetes mellitus.Endocr. Rev. 2022; 43: 314-328Crossref PubMed Scopus (34) Google Scholar, 19.Quarta C. et al.POMC neuronal heterogeneity in energy balance and beyond: an integrated view.Nat. Metab. 2021; 3: 299-308Crossref PubMed Scopus (48) Google Scholar,64.Garcia-Caceres C. et al.Role of astrocytes, microglia, and tanycytes in brain control of systemic metabolism.Nat. Neurosci. 2019; 22: 7-14Crossref PubMed Scopus (140) Google Scholar]. 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